MULTIPLE EXPOSURES TO SEVOFLURANE DURING THE NEONATAL PERIOD IMPAIR HIPPOCAMPUS DEVELOPMENT AND COGNITIVE FUNCTION IN YOUNG MICE

Abstract

Background: Sevoflurane is a commonly used anesthesia for infants and young children. Sevoflurane has potential neurotoxicity in immature brains; however, its specific mechanism remains unclear. Methods: C57BL/6J mice were randomly divided into sevoflurane and control groups. Mice in the sevoflurane group were anesthetized with 2.5% sevoflurane for 2 h daily at postnatal days 6‒8. Mice in the control group did not receive sevoflurane anesthesia. On day 3 of modeling, half of the mice were randomly selected to undergo harvesting of the hippocampus. Results: RNA sequencing of RNA extracted from the hippocampus identified 736 differentially expressed genes (433 upregulated and 303 downregulated). Gene ontology term enrichment analysis results suggested that sevoflurane exposure altered the expression of neurodevelopment-related genes in neonatal mice. Enriched biological processes included brain development and adenosine monophosphate-activated protein kinase signaling pathways. Differentially expressed genes of the neonatal hippocampus after multiple exposures to sevoflurane were specific to neonatal mice. Morris water maze testing confirmed that sevoflurane anesthesia-induced learning and memory impairments in young mice. Western blot and immunofluorescence analyses showed that sevoflurane treatment decreased synaptic protein levels, such as postsynaptic density protein 95, synaptosomal-associated protein and B-cell lymphoma 2-associated athanogene 3, in the hippocampus, which induced synaptic dysfunction, resulting in impaired nervous system development in young mice. Conclusions: This study provides a better understanding of and potential explanation for the mechanisms of the impact of anesthesia on brain function in young mice exposed to sevoflurane.